The
Western
Journal
of
Medicine
Coichicine
Use
for
Familial
Mediterranean
Fever
Observations
Associated
With
Long-term
Treatment
ROBERT
S.
PETERS,
MD,
Fresno,
California;
THOMAS
J.
A.
LEHMAN,
MD,
Bethesda,
Maryland,
and
ARTHUR
D.
SCHWABE,
MD,
Los
Angeles
Of
85
patients
with
familial
Mediterranean
fever
receiving
continuous
prophylactic
col-
chicine
therapy,
62
(73
percent)
have
had
a
significant
reduction
in
the
severity
and
frequency
of
their
attacks.
All
62
have
been
observed
for
three
years
or
more,
for
a
total
of
4,680
patient-months
and
a
mean
duration
of
75.5
months.
Of
the
85
patients,
23
(27
percent)
did
not
complete
three
years
of
treatment
for
a
variety
of
reasons.
Diarrhea
was
the
most
common
side
effect,
necessitating
reduction
of
colchicine
dosage
in
12
patients,
but
discontinuation
of
treatment
in
only
one.
No
other
significant
side
effects
were
ob-
served.
Continuous,
prophylactic
colchicine
therapy
is
effective
in
preventing
the
recurrent
febrile
paroxysms
of
familial
Mediterranean
fever
and
is
indicated
in
those
patients
who
are
incapacitated
by
frequent
attacks
or
who
are
at
risk
for
amyloidosis
developing.
The
efficacy
of
prophylactic,
continuous
colchicine
therapy
in
preventing
the
recurrence
of
febrile
at-
tacks
of
familial
Mediterranean
fever
was
established
by
three
controlled
studies
in
19741-3
and
later
con-
firmed
by
reports
from
several
centers.4-6
Between
the
years
1967
and
1978
a
total
of
99
patients
with
familial
Mediterranean
fever
from
the
clinics
of
two
California
hospitals
were
selected
to
receive
continuous
colchicine
therapy.
The
subsequent
course
of
these
patients,
in-
cluding
adherence
to
the
recommended
regimen,
dosage
and
side
effects,
and
the
long-term
efficacy
of
the
treat-
ment
in
preventing
attacks,
constitutes
the
basis
of
this
report.
Methods
The
diagnosis
of
familial
Mediterranean
fever
in
all
patients
in
this
study
was
based
on
established
cri-
teria.4'7
The
99
patients
included
62
Armenians,
30
Jews
and
7
of
other
ethnic
origin.
There
were
56
male
and
43
female
patients,
ranging
in
age
from
4
to
64
years,
Indications
for
administering
continuous
colchi-
cine
therapy
were
one
or
more
of
the
following:
frequent,
severe
attacks
significantly
interfering
with
a
normal
pat-
tern
of
life;
failure
of
alternative
therapy,
and
a
family
history
of
familial
Mediterranean
fever
amyloidosis.
The
patients
were
informed
of
the
indications
for
col-
chicine
therapy,
possible
side
effects
and
potential
bene-
fits.
Patients
with
a
reproductive
potential
were
also
advised
to
interrupt
the
colchicine
therapy
before
a
planned
conception.
Initially,
a
dosage
of
0.5
or
0.6
mg
of
colchicine
twice
a
day
was
recommended,
but
the
dosage
was
increased
to
0.6
mg
three
times
a
day
for
all
patients
older
than
16
years
of
age
in
1974.
Patients
were
observed
at
regular
intervals
and
ques-
tioned
about
adherence
to
the
regimen,
symptoms,
fre-
quency
of
attacks
and
side
effects.
A
physical
examina-
tion
and
a
qualitative
test
for
urine
protein
were
carried
out
at
each
visit.
Routine
blood
counts
were
done
before
Refer
to:
Peters
RS,
Lehman
TJA,
Schwabe
AD:
Colchicine
use
for
familial
Mediterranean
fever-Observations
associated
with
long-term
treatment.
West
J
Med
1983
Jan;
138:43-46.
From
the
Departments
of
Medicine,
UCLA
School
of
Medicine,
Los
Angeles,
and
Valley
Medical
Center
of
Fresno;
and
the
Department
of
Pediatrics,
University
of
California,
San
Diego.
Dr
Lehman,
formerly
with
the
Department
of
Pediatrics,
University
of
California,
San
Diego,
is
now
affiliated
with
the
National
Institute
of
Arthritis,
Digestive
and
Kidney
Diseases,
Bethesda,
Maryland.
Submitted
April
29,
1982.
Reprint
requests
to
Arthur
D.
Schwabe,
MD,
Department
of
Medicine,
UCLA
School
of
Medicine,
Los
Angeles,
CA
90024.
JANUARY
1983
*
138
*
1
43
PROPHYLACTIC
COLCHICINE
USE
and
at
the
time
of
two
or
more
subsequent
monthly
clinic
visits.
Results
Duration
of
Treatment
The
course
of
the
99
patients
originally
entered
in
the
study
is
outlined
in
Table
1.
Two
patients
died
of
causes
unrelated
to
familial
Mediterranean
fever
or
treat-
ment
and
12
were
lost
to
follow-up.
Of
the
remaining
85
patients
available
for
analysis,
62
(73
percent)
have
continued
to
take
colchicine
for
three
or
more
years.
The
mean
duration
of
treatment
as
of
April
1981
was
75.5
months,
with
a
range
of
36
to
169
months
(Figure
1).
A
total
of
42
patients
have
completed
five
or
more
years
of
continuous
colchicine
therapy.
Of
the
85
patients
23
(27
percent)
interrupted,
dis-
continued
or
were
withdrawn
from
therapy
for.
reasons
shown
in
Table
1
and
detailed
later
in
this
report.
Eight
patients-who
were
apprehensive
about
the
possible
side
effects
of
colchicine-used
the
drug
sporadically
or
discontinued
using
it
entirely
and
were
therefore
classified
as
noncompliant.
One
patient
was
withdrawn
from
colchicine
therapy
due
to
chronic
diarrhea
that
became
intractable
when
quinidine
had
to
be
added
to
his
regimen
because
of
a
coexistent
arrhythmia.
In
a
second
patient,
a
44-year-old
man
who
had
been
suc-
cessfully
treated
for
three
years,
a
progressive
decrease
in
libido
developed.
He
attributed
this
to
the
colchicine
therapy
and
discontinued
taking
the
drug.
A
third
pa-
tient,
a
22-year-old
man
who
had
been
successfully
TABLE
1.-A
Long-term
Study
of
Coichicine
Therapy
for
Familial
Mediterranean
Fever
Showing
Degree
of
Compliance
to
Recommended
Regimen
Description
of
Patients
No.
No.
(percent)
Entered
in
study
......................
99
Removed
from
study
...................
14
Died
(unrelated
to
FMF)
.....
.......
2
Lost
to
follow-up
..........
...........
12
Followed
regularly
.....................
85
(100)
Did
not
complete
full
course
of
therapy
...
23
(
27)
Did
not
comply
with
regimen
.....
.....
8
Therapy
withdrawn
because
of
side
effects
3
Failed
to
respond
to
colchicine
.....
....
12
Completed
>3
years
of
therapy
..........
62
(
73)
Duration
of
Therapy
30[
25
cn
z
'LI
lLi
a.
U-
0
d
z
20F
15
10
5
36-
48-
47
59
MONTHS
60-
72-
71
83
OF
CONTINUOUS
84-
96-
95
107
THERAPY
>107
Figure
1.-Duration
of
continuous,
daily
colchicine
treatment
in
62
patients
with
familial
Mediterranean
fever.
(I,
z
LiJ
,.,
0
ci
z
Current
Dosage
D.
L
D.O
(mg.
DAILY
DOSE
(mg)
Figure
2.-Current
daily
coichicine
dosage
in
62
patients
with
familial
Mediterranean
fever
on
long-term
treatment.
treated
for
more
than
five
years,
was
advised
to
inter-
rupt
therapy
when
he
decided
to
start
a
family.
These
three
patients
did
not
complete
the
prescribed
course
of
therapy
because
of
actual,
presumed
or
potential
side
effects.
Eight
patients
with
coexistent
functional
or
psycho-
logical
disorders
continued
to
have
a
variety
of
symp-
toms,
such
as
chronic
abdominal
pain,
weakness
and
headaches,
which
were
unaffected
by
taking
colchicine.
In
three
patients
who
were
found
to
be
addicted
to
narcotics
and
who
continued
to
complain
of
symptoms,
neither
the
efficacy
nor
the
adherence
to
the
prescribed
regimen
could
be
verified.
An
additional
patient
re-
ported
no
change
in
the
frequency
and
severity
of
his
attacks
while
taking
colchicine.
These
12
patients
were
classified
as
treatment
failures
(Table
1).
Dosage
of
Colichicine
From
1967
to
1974
patients
were
maintained
on
a
regimen
of
1.0
to
1.2
mg
of
colchicine
per
day.
Sub-
sequently,
however,
a
dosage
of
1.8
mg
(0.6
mg
three
times
a
day)
was
prescribed
for
all
adults
entering
the
study
for
optimal
suppression
of
attacks.
The
effects
of
familial
Mediterranean
fever
were
controlled
in
six
chil-
dren
with
the
administration
of
1.2
mg
a
day.
The
dosage
was
reduced
to
1.2
mg
a
day
in
22
adult
patients.
Reduc-
tion
was
necessitated
in
12
patients
due
to
side
effects,
which
will
be
detailed
later
in
this
report.
The
other
ten
patients
voluntarily
reduced
their
dosage
on
advice
from
other
family
members
or
friends
who
were
doing
well
on
a
lower
dosage,
or
because
they
forgot
to
take
the
midday
dose
and
seemed
to
notice
no
ill
effect.
No
patients
were
maintained
on
less
than
1.2
mg
a
day.
The
colchicine
dosage
was
increased
to
2.4
mg
a
day
in
two
patients
whose
attacks
were
partially,
but
not
completely,
suppressed
on
the
lower
dosage.
The
THE
WESTERN
JOURNAL
OF
MEDICINE
44
LM
L7
PROPHYLACTIC
COLCHICINE
USE
Effec
:V)
z
LLJ
0
z
NO.
Figure
3.-Long-term
E
familial
Mediterranean
phylactic
colchicine.
:t
on
Frequency
of
Attacks
the
addition
of
a
psyllium
seed
preparation
and
a
third
to
the
administration
of
diphenoxylate
hydrochloride
7
Before
,8
with
atropine.
Three
patients
continued
to
have
in-
During
-
creased
frequency
of
bowel
movements,
but
prefer
this
side
effect
to
recurrent
attacks
of
familial
Mediterra-
nean
fever.
The
13th
previously
cited
patient
with
in-
tractable
diarrhea
after
the
addition
of
quinidine
had
to
be
withdrawn
from
colchicine
therapy.
In
four
patients
transient,
self-limited
anorexia
and
H
r
|
nausea
developed,
but
no
vomiting.
No
weight
loss,
1-4
--
1
,weakness,
myopathy,
hair
loss,
abortions,
anemia,
leu-
-
4
5-8
9-
12
>"
,
kopenia
or
steatorrhea
was
observed
in
any
of
the
pa-
tients.
Small
intestinal
biopsies
are
being
carried
out
in
OF
ATTACKS
PER
YEAR
a
number
of
the
patients;
preliminary
results
do
not
effect
on
the
frequency
of
attacks
of
indicate
any
significant
histologic
abnormalities.
Except
fever
in
62
patients
taking
daily,
pro-
for
one
patient
mentioned
previously,
no
one
reported
libidinal
disturbances
or
infertility.
None
of
the
women
or
sexual
'artners
of
the
men
in
this
studv
became
amount
of
colchicine
currently
taken
by
the
62
pa-
tients
is
shown
in
Figure
2.
Effect
of
Colchicine
Therapy
on
Attacks
All
of
the
62
(73
percent)
patients
still
receiving
colchicine
therapy
in
April
1981
had
a
significant
reduc-
tion
in
the
severity
and
frequency
of
their
attacks,
as
shown
in
Figure
3.
In
all,
39
patients
ceased
to
have
attacks
for
the
period
of
study-that
is,
more
than
three
years-and
22
patients
had
only
one
to
four
attacks
a
year.
None
of
the
treated
patients
required
hospital
admission
for
familial
Mediterranean
fever
during
the
period
of
treatment.
This
attack
frequency
is
in
sharp
contrast
to
the
number
of
attacks
occurring
before
the
institution
of
therapy.
Of
the
85,
there
were
23
(27
percent)
who
failed
to
complete
three
years
of
therapy
or
had
terminated
therapy
before
April
1981
for
the
reasons
previously
mentioned.
Although
several
of
these
patients
clearly
benefited
from
taking
the
drug,
all
were
considered
long-term
treatment
failures.
It
should
be
stressed,
however,
that
for
patients
with
familial
Mediterranean
fever,
treatment
requires
a
flexible,
multifaceted
ap-
proach
that
takes
into
account
the
tendency
of
addic-
tion
to
narcotics,
the
coexistence
of
other
physical
and
emotional
disorders
and
the
concern
about
long-term
side
effects
of
colchicine
use
and
its
potential
harmful
effects
on
conception.
Any
of
these
problems
may
result
either
in
noncompliance
or
failure
of
colchicine
therapy.
Side
Effects
Virtually
all
patients
had
mild,
transient
diarrhea
and
abdominal
discomfort
for
one
to
three
days
after
the
institution
of
treatment.
However,
13
patients
con-
tinued
to
have
two
to
four
loose
or
watery
bowel
move-
ments
a
day
for
more
than
a
month.
In
6
of
the
13
patients,
reducing
the
colchicine
dosage
from
1.8
to
1.2
mg
a
day
resulted
in
a
return
to
normal
bowel
habits.
The
other
seven
patients
did
not
improve
with
reduc-
tion
in
drug
dosage
alone.
Two
of
them
responded
to
pregnant
during
the
study
period.
Discussion
During
the
past
seven
years
continuous,
prophylactic
colchicine
therapy
has
significantly
improved
the
man-
agement
and
prognosis
of
patients
with
familial
Medi-
terranean
fever.'-
The
long-term
follow-up
study
pre-
sented
here
shows
not
only
that
this
form
of
treatment
continues
to
be
effective,
but
also
that
it
is
relatively
free
of
significant
side
effects.
Administration
of
the
drug
had
to
be
discontinued
in
only
one
patient
because
of
intractable
diarrhea.
In
dosages
of
more
than
1.8
mg
a
day
colchicine
may
cause
malabsorption
of
fat,
D-xylose
and
vitamin
B,2,
as
well
as
inhibition
of
intestinal
enzymes,8'9
compli-
cations
not
observed
in
our
patients.
In
even
larger
doses,
colchicine
may
be
toxic
to
gastrointestinal
mucosa,
bone
marrow,
kidneys,
lungs
and
cardiovascular
system.10-'2
Such
severe
toxicity,
however,
occurs
most
often
after
accidental
overdoses
or
suicide
attempts
in
patients
who
have
received
7
to
350
mg
of
colchicine
in
rela-
tively
short
periods
of
time.'3
The
relative
safety
of
recommended
daily
dosages
of
colchicine
(that
is,
1
to
1.8
mg)
has
been
emphasized
in
other
articles.5"14
Nevertheless,
we
continue
to
be
concerned
about
the
effect
of
colchicine
on
fertilization,
implantation
and
pregnancy
and
advise
our
patients
to
stop
taking
the
drug
three
months
before
planned
conception.
Wright
and
co-workers15
found
that
three
of
five
patients
who
had
premonitory
symptoms
could
abort
an
attack
by
taking
6
mg
of
colchicine
in
divided
doses
over
72
hours.
This
intermittent
therapy
is
difficult
for
most
patients.
Many
cannot
clearly
recognize
the
earli-
est
signs
of
an
attack
and
wait
until
the
attack
is
well
established
and
no
longer
amenable
to
colchicine
sup-
pression.
Others
start
taking
colchicine
for
unrelated
symptoms,
especially
upper
respiratory
tract
infections
and
functional
abdominal
pain,
and
wrongly
conclude
that
the
drug
is
totally
ineffective.
Another
strong
argu-
ment
for
continuous
colchicine
therapy
is
its
possible
beneficial
effect
on
amyloidosis.
Early
evidence
suggests
JANUARY
1983
*
138
*
1
45
F
PROPHYLACTIC
COLCHICINE
USE
that
colchicine
therapy
may
prevent,
reverse
or
impede
the
progression
of
amyloidosis.14
16
At
present,
there-
fore,
there
is
little
question
that
those
ethnic
groups
at
high
risk
for
amyloidosis
developing
should
be
receiv-
ing
continuous
colchicine
therapy.
Colchicine
administration
has
been
used
with
vari-
able
success
in
several
other
clinical
disorders
such
as
gout,
pseudogout,
Behget's
disease,
necrotizing
vasculi-
tis,
scleroderma
and
Paget's
disease,
but
little
is
known
about
its
mechanism
of
action.
Although
interference
with
microtubule
formation,
degranulation
of
neutro-
phils
and
alteration
of
leukocyte
adenosine
3':5'-cyclic
phosphate
levels
have been
found
in
vitro,
the
relevance
of
these
effects
to
colchicine
prophylaxis
for
familial
Mediterranean
fever
is
unclear.'7"18
REFERENCES
1.
Zemer
D,
Revach
M-,
Pras
M,
et
al:
Controlled
trial
of
colchicine
in
preventing
attacks
of
familial
Mediterranean
fever.
N
Engl
J
Med
1974;
291:932-934
2.
Dinarello
CA,
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Medical
Practice
Questions
EDITOR'S
NOTE:
From
time
to
time
medical
practice
questions
from
organizations
with
a
legitimate
interest
in
the
information
are
referred
to
the
Scientific
Board
by
the
Quality
Care
Review
Commission
of
the
California
Medical
Association.
The
opinions
offered
are
based
on
training,
experience
and
literature
reviewed
by
specialists.
These
opinions
are,
however,
informational
only
and
should
not
be
interpreted
as
directives,
instructions
or
policy
state-
ments.
Transcutaneous
Electrical
Nerve
Stimulation
(TENS)
and
Percutaneous
Electrical
Nerve
Stimulation
(PENS)
and
Electroacutherapy
QUESTIONS:
Has
the
use
of
transcutaneous
electrical
nerve
stimulation
(TENS)
or
percutaneous
electrical
nerve
stimulation
(PENS)
for
the
relief
of
pain
become
accepted
medical
practice,
or
are
they
investigational?
Is
it
accepted
medical
practice
to
use
electroacutherapy
modalities
in
conjunction
with
either
transcutaneous
electrical
nerve
stimulation
or
percutaneous
stimulation?
OPINION:
In
the
opinion
of
the
Advisory
Panels
on
Internal
Medicine,
Neurology,
Neuro-
surgery
and
Physical
Medicine
and
Rehabilitation,
transcutaneous
electrical
nerve
stimulation
(TENS)
and
percutaneous
electrical
nerve
stimulation
(PENS)
have
been
accepted
as
established
therapeutic
modalities
for
the
relief
of
pain.
TENS
iS
acceptable
treatment
for
acute
as
well
as
chronic
pain,
primarily
of
musculoskeletal
or
neurological
etiology.
PENS
is
also
acceptable
treatment
but
because
of
asso-
ciated
risks
it
should
be
reserved
for
chronic,
intractable
pain
conditions.
Electroacutherapy
modalities
used
in
conjunction
with
either
TENS
or
PENS
for
relief
of
pain
are
not
established
medical
practice.
Further
investigation
is
required
to
determine
their
safety
and
efficacy
in
patients
with
pain
syndromes
or
other
con-
ditions.
Such
research
should
be
carried
out
under
a
strict
scientific
protocol.
THE
WESTERN
JOURNAL
OF
MEDICINE
46
